The objective of this research proposal is the study of development of resistance to several antibotics in Streptococcus pneumoniae. The problem will be approached from two different angles: 1) genetic basis for development of resistance and 2) biochemical mechanisms. Preliminary genetic studies have already shown that in the South African pneumococci (multiple antibiotic resistant) oxacillin-resistance is a property acquired in a stepwise process and is mediated by at least four different genetic units which depend on each for the manifestation of high levels of resistance. The possibility that antibiotic resistance in these strains might be a plasmid-mediated phenomenon will also be investigated. On the biochemical level, the studies on the intrinsic resistance of these pneumococci will be focused on possible alterations in the pneumococcal envelope components, namely peptidoglycan, wall teichoic acid, lipid-teichoic acid and plasma membrane; and on qualitative or quantitative changes in the nature, accessibility of beta lactam affinity of pneumococcal penicillin binding proteins. Additional studies are planned to determine the prevalence of resistance among pneumococci in different patient populations.